Two sequential cohorts of patients were enrolled (Figure 1) Befo

Two sequential cohorts of patients were enrolled (Figure 1). Before randomization, patients had to complete 2 separate screening ETTs (ETT1 and ETT2) administered at least 24 h apart, achieving ≥4 min of a Modified Naughton Exercise Protocol on both tests (Online Methods). Baseline ETT performance was defined as the shorter of the 2 exercise durations recorded during the screening ETTs. Patients in each cohort were randomly

assigned in a 2:1 ratio to receive an IV infusion of omecamtiv mecarbil or placebo over 20 h. A third ETT (ETT3) was performed during the final 2 h of IV dosing. Patients in the omecamtiv mecarbil arms were dosed to target plasma levels of ∼295 ng/ml in cohort 1 (24 mg/h for 2 h followed by 6 mg/h for 18 h) and ∼550 ng/ml in cohort 2 (48 mg/h for 2 h followed by 11 mg/h for 18 h). Patients who tolerated the IV infusion then self-administered omecamtiv mecarbil orally (immediate release; 12.5 mg and 25 mg for cohorts 1 and MLN8237 datasheet 2, respectively) or

placebo orally 3 times daily for 7 days. Patients had a follow-up visit 6 to 14 days after the last oral dose. There were no exercise tests during or after oral dosing. In each cohort, patients were assigned to treatment via central randomization by an independent vendor. An unblinded site pharmacist prepared the study medications and provided them to blinded site staff according to the randomization system assignment. Core laboratories were used GBA3 for analysis of echocardiograms (ICON Medical Imaging, Warrington, Pennsylvania) and exercise electrocardiograms

(ECGs) (St. Louis University Core ECG Lab, St. Louis, Missouri). Two local core laboratories were used to analyze blood samples for cardiac enzymes (INVITRO Central Laboratory, Moscow, Russia; Medical Center CITO Ltd, Tbilisi, Georgia). The upper reference limit for assays performed by Medical Center CITO was ≥0.11 μg/l and for INVITRO was ≥ 1 μg/l; the limit of detection for Medical Center CITO assays was 0.01 μg/l, and it was not specified for the INVITRO assays. The primary endpoint of this safety study was the proportion of patients who stopped ETT3 because of angina and at a stage earlier than baseline. Secondary safety endpoints included the proportion of patients who stopped ETT3 for any reason at a stage earlier than baseline; duration of exercise during ETT3; proportion of patients with angina during ETT3; time to angina during ETT3; proportion of patients with 1-mm ST-segment depression on their ECG during ETT3; time to 1-mm ST-segment depression during ETT3; and AEs and serious adverse events (SAEs).

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